3alpha, 4alpha and 5beta, 6beta-cyclopropanopregnene derivatives



United States Patent 3,080,385 30540: AND SflfiB-QYCLGPROPANO- PREGNENE DERIVATIVES Lawrence H. Knox, Mexico City, Mexico, assignor to Syntex S.A., Mexico City, Mexico, a corporation of Mexico No Drawing. Filed Apr. 13, 1962, Ser. No. 187,201

20 Claims. (Cl. 260-3971) CHzOR CHECK i x-o x-o x x onion CH2OR =0 i=0 CH-OOOR OH-OOOR In the above formulas X represents hydrogen, fluorine or chlorine; Y represents a keto group or a [3-hydroxyl; R represents hydrogen or a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; and R represents hydrogen or a lower alkyl group.

The acyl group is derived from hydrocarbon carboxylic acids containing less than 12 carbon atoms which may be saturated or unsaturated, of straight, branched, cyclic or cyclic-aliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethyl acetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate and e-chloropropionate.

The compounds represented by the above formulas possess anti-androgenic, anti-estrogenic, anti-gonadatrophic, anti-inflammatory and glycogenic properties.

The novel compounds of the present invention are prepared by the process exemplified as follows:

onion OHQOR rro %]::O

on ---OH C I (VIII) (IX) biz-coon GEL-COOK In the above formulas X, Y, R and R have the same meaning as set forth hereinbefore;

The starting compound (I) of the process just outlined, is 17,20;20,21 bismethylenedioxy-A -pregnadien-11 3-01 and is prepared from hydrocortisone by conventional treatment with formaldehyde in the presence of hydrochloric acid, reduction of the resulting l7,20;20,2l-bismethylenedioxy-M-pregnen-11,8-01-3-one, preferably with lithium aluminum hydride and finally refluxing the obtained 17,20;20,21-bismethylenedixy-A -pregnen-3B,1 118- diol with 50% acetic acid.

In carrying out the process illustrated above, the starting compound (I) is treated with an alkali metal trichloroacetate, preferably sodium trichloroacetate, in a suitable solvent such as bis-(2-methoxyethyl) ether at approximately 125 C. for a period of time of the order of 1.5 hours and the product thus obtained is chromatographed, for example on Florisil, thus affording 17,20;20, 2l-bisrnethylenedioxy-l,l-dichlorocyclopropano (2,3; 3a,4a)-A -pregnen-1'l[3ol (-II: X=C1, Y=/3-OH) and 17,20;20,2Lbismethylenedioxy 1,l dichlorocyclopropano-(2,3';5 8,6B)-A -pregnen-11fi-ol (III: X=C1, Y=fi- OH).

Upon treatment of the starting compound (I) with diazomethane in the presence of copper powder followed by chromatography of the resulting product, there are obtained 17,20;20,2l bismethylenedioxycyclopropano- (1,2;3a,4a)-A -pregnen-1lfi-ol (I-I: X H, Y-=fi-OH) and l7,20;20,21-bismethylenedioxy-cyclopropano (l,2'; 5B,6fi)-A -pregnen-l1fi-ol (III: X=H, Y=,8-OH).

Upon reaction of the starting compound (I) with an alkali metal monochlorodifluoroacetate, preferably sodium monochlorodifiuoroacetate, in a suitable solvent such as diglyme, at reflux temperature, for a period of time of the order of 20 minutes, followed by chromatography of the resulting product,-there are produced 17,20;20,21-bismethylenedioxy-l,l-difiuorocyclopropano (2',3';3 u,4a) n -pregnen-llfi-ol (II: X=F, Y=}9-OH) and 17,20;20,2lbismethylenedioxy-l',l-difiuorocyclopropano (2,3;5fl, 65)-A -pregnen-11/3ol (III: X=F, Y= 8-OI-I).

The reaction of the starting compound (I) with a lower alkyl diazoacetate such as ethyl diazoacetate, in the presence of copper powder in a suitable solvent such as 1,2- dirnethoxy-ethane, at reflux temperature and for a period of time of the order of 4.5 hours, yields a product which upon chromatography is separated into 17,20;20,21-bisrnethylenedioxy 1' carbethoxycyclopropano (2',3';3o, 4a)-A -pregnen-1 1 8-01 (IV: Y=13-OH, R =ethyl) and 17,20;20,2 1-bismethylenedioxy 1' carbethoxycyclopropano (2',3;5B,6fl) A pregnen-llfi-ol (V: Y==fl-OH, R ethyl). Conventional saponification of the latter compounds with a base, affords the corresponding 1- carboxycyclopropane derivatives (IV, V: R '=H).

The above described llfl-alcohols (II, III, IV, V: :B-OH) areoxidized, preferably with chromic acid, to the corresponding 11-ketones (II, III, IV, V: .Y=O).

All the above compounds which have a 17,20; 20,21- bismethylenedioxy grouping, are conventionally hydrolyzed in an acid medium such as 60% formic'acid, to give 4 the corresponding 17a,21diol-20-one derivatives (VI, VII, VIII, IX: R=H).

The Zl-hydroxyl of the obtained free 17a,21-diol-20- one derivatives is conventionally acylated in pyridine, thus giving the corresponding 2l-acylates (VI, VII, VIII, IX: R=acyl).

The following specific examples serve to illustrate but are not intended to limit the scope of the present invention:

PREPARATION 1 To a solution of 5 g. of hydrocortisone in 200 cc. of chloroform were added 40 cc. of 37% aqueous formaldehyde and 5 cc. of concentrated hydrochloric acid and the mixture was stirred for 48 hours at room temperature. The .two layers were separated; the aqueous layer was washed with chloroform and the combined organic solutions were Washed with water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was recrystallized from methanol-ether thus affording l7,20;2O,2l-bismethylenedioxy A pregnen-11l3- ol-3-one.

A solution of 4 g. of the latter compound in 250 cc. of tetrahydrofuran was added over a 30 minute period to a stirred suspension of 4 g. of lithium aluminum hydride in 250 cc. of anhydrous tetrahydrofuran. The mixture was refluxed for 2 hours, then cooled and cautiously treated with 15 cc. of ethyl acetate and 8 cc. of water. Solid sodium sulfate was added, the inorganic material filtered oil? and thoroughly washed with hot ethyl acetate, the combined organic solutions upon evaporation yielded a crude material, which was purified by crystallization from acetone-hexane thus giving l7,20;20,2l -bismethylenedioxy-M-pregnen-Ziflllfi-diol.

1 g. of 17,20;20,21-bismethylenedioxy-A pregnene-318, llB-diol was heated on the steam bath with cc. of 50% acetic acid under nitrogen for 1 hour, it was then concentrated under vacuum to a small volume and poured into water. The precipitate was collected, washed well with Water, dried and recrystallized from acetonehexane, thus furnishing 17,20;20,2l-bismethylenedioxy-M' -pregnadien-l 113-01.

Example I To a solution of 2 g. of 17,20;20,2l-bismethylenedioxy A -pregna'dien-1lfl-ol in 50 cc. of diglyme [bis(2-methoxyethyl)ether] at C. there were added 4.4 g. of sodium trichloroacetate in 10 equal portions at 10 minute intervals. The reaction mixture was then cooled; the formed sodium chloride filtered off and the filtrate evaporated to dryness under reduced pressure. The residue was conventionally chromatographed on Florisil, thus yielding two products, which upon crystallization from methanol furnished l7,20; 20,2l-bismethylenedioxy-l',ldichlorocyclopropano '(2,3';3a,4a) A pregnen-llfi-ol and 17,20;20,21 bismethylenedioxy 1,l'-dichlorocyclopropano-(2',3';5,B,6;3)-A -pregnen-11,8-01.

Example 11 To a mixture of 2 g. of 17,20; 20,21-bismethylenedioxy- A -pregnadien-llfi-ol, 50 cc. of ether and 300 mg. of powdered copper there was cautiously added a large excess of an ethereal solution of diazomethane, dropwise and with stirring. After evolution of nitrogen had ceased, the mixture was filtered and the excess reagent was decomposed'by adding dropwise acetic acid until the yellow color of the filtrate disappeared. The solution was then evaporated to dryness and the residue chromatographed on Florisil, thus yielding two products which upon crystallization from acetone-hexane furnished 17,20;20,21-bismethylenedioxy cyclopropano-(1,2;3a,4ot)-A -pregnen- 1119-01 and '17,20;20,21-bismethylenedioxy-cyclopropano- (1?,2;5,B,6/3)A -pregnen-llfl-ol.

, Example 111 A mixture of 2 "g. of 17,20;20,21 bismethylenedioxy A -pregnadien-1lB-ol, 20 cc. of 1,2-dimethoxyethane and 300 mg. of freshly prepared copper powder was heated to reflux temperature, then there was added dropwise with stirring a solution of 3.4 g. of ethyl diazoacetate in cc. of 1,2-dimethoxy-ethane over a period of 2 hours. Refluxing was continued for an additional 2.5 hours. The catalyst was thereafter filtered off and the filtrate evaporated to dryness. The residue was conventionally chromatographed on Florisil, thus yielding two products which upon crystallization from acetone-hexane furnished 17,20; 20,21 bismethylenedioxy l carbethoxycyclopropano- (2,3';3ot,4ot)-A -pregnen-1lfi-ol and 17,20;20,21-bismethylenedioxy-l-carbethoxycyclopropano (2,3;5}3,6B)-A pregnen-l 1,8-01.

Example IV A mixture of 2 g. of l7,20;20,2l-bismethylenedioxy- A -pregnadien-11fl-ol, 100 cc. of diglyme and 4 g. of sodium monochlorodifluoroacetate was refluxed for minutes, then cooled to 50 C., an additional 4 g. of the same salt were thereafter added and the resulting mixture again refluxed for 10 minutes. The reaction mixture was cooled, the formed sodium chloride filtered off and the filtrate evaporated to dryness under reduced pressure. The residue was conventionally chromatographed on Florisil, thus yielding two products, which upon crystallization from methanol furnished 17 ,20;20,21-bismethylenedioxy-l',l'-difluorocyclopropano (2',3';3tx,4a) A -pregnen-llfl-ol and 17,20;20,21 bismethylenedioxy 1',1-difluorocyclopropano- (2,3 ;5,6,6,B) -A -pregnen-l 119-01.

Example V A solution of 1 g. of 17,20;20,2l-bismethylenedioxy- 1',1'-dichlorocyclopropano-(2,3;3a,4ot) A pregnen- 11,8-01 in 10 cc. of acetone was cooled to 0 C'. and treated under an atmosphere of nitrogen and with stirring, with a solution of 8 N chromic acid (prepared by mixing 26 g. of chromium trioxide with 23 cc. of concentrated sulfuric acid and diluting with water to 100 cc.), until the color of the reagent persisted in the mixture. It was stirred for 5 minutes further at 0-5" C. and diluted with water. The precipitate was collected, washed with water and dried under vacuum, thus affording a crude product which upon recrystallization from acetone-hexane gave 17,20;20,2l-bismethylenedioxy-1',1- dichlorocyclopropano- 2',3 ;3 06,406)-A -PIegI16n-11"OIle.

Following the same procedure, the starting compounds listed under I were converted into the corresponding products set forth under II.

Example VI 6 propano-(2',3';3a,4a)-A -pregnene 11,6,l7a,21 s triol-20- one.

' The starting compounds under I were submitted to the same treatment, thus producing the corresponding products under II.

17,20; 20,21-bismcthylenedioxy- 1, 1-dich10rocyclo pro pano- (2 3 55,63)-A -pregnen-11-one.

17,20; 20,2l-bismethylenedtoxyeyclopropano-(1,2; 3a,4a)-A prognendl-one.

17,20; 20,21-blsmethylencdioxycyclopropano-(1,2; 5B,6B)-A pregnen-ll-onc.

17,20; 20,21-bismethylene lioxy-1'- earbethoxyeyclopropano-(2,3'; 3a,4a)-A -pregnen-11-one.

17,20; 20,2l-bismethylenedioxy-1- carbethoxycyclopropano-(2,3; 5,8,0B)-A -pregnen-11-one.

17,20; 20,21-bismethy1enedioxy- 1,l-difluorocyclopropano-(2,3; 301,401)-A -prgeneu-11-one.

17,20; 20,2l-bismcthylenedioxy- 1,1-ditlnorocyclopropano-(2,3; 53,68)-A -pregnen-1l-one.

17,20;20 21-bisrnethylenedioxy- 1,1-diehlorocyclopropano-(2,3; 3 m)-A -preguen-11-one.

17,20; 20,21-bismethylenedioxy- 17,20; 2O,21-bismethylenedioxy-Y- 17,20; 20,2l-bismethylenedioxy-l'- earbethoxycyclopropano-(2,3;

65,65)-A -pregnen-11B-o1.

17,20; 20,21-bismethylenedioxy- 1,1-difiuorocyelopropano-(2,3; 58.6Bl-M-Dregnen-11B-ol.

Example VII A mixture of 1 g. of 1,1'-dichlorocycl0propano- (2',3',3a,4ot)-A -pregnene-11fl,17a,21-triol-20-one, 4 cc. of pyridine and 2 cc. of acetic anhydride was kept at room temperature overnight, poured into ice water, the

formed precipitate was filtered, washed with water and dried. Crystallization from acetone-hexane gave the 21- acetate of 1,1'-dichlorocyclopropano(2,3';3a,4a)-A pregnene-llB,17a,21-triol-20-one.

The same conditions were used for the conversion of the rest of the final products of Example VI into the corresponding 21-acetates.

Example VIII The final products of Example VI were treated in accordance with Example VII, except that acetic anhydride was substituted by propionic anhydride and caproic anhydride, thus afiording respectively the corresponding 21- propionates and ZI-caproates.

Example IX A suspension of 1 g. of 1'-carbethoxycyclopropano- (2,3;3a,4u)-A -pregnene-17a,21-diol-11,20-di0ne in 60 cc. of methanol was treated with a solution of 1 g. of potassium carbonate in 6 cc. of water; the mixture was boiled under reflux for 1 hour and then cooled in ice and diluted with water. The formed precipitate was collected and recrystallized from acetone-hexane to yield 1' carboxycyclopropano (2',3';3a,4a) A pregnene- 17a,21-di0l-11,20-(li0I16.

1' carbethoxycyclopropano-(Z',3';5,3,6fl)-A -pregnene- 1701,21 diol 11,20 dione, 1-carbethoxycyclopropano- (2,3';3a,4a)-A -pregnene-11,3,l7a,21-triol-20-one and 1'- carbethoxycyclopropano (2',3';5,B,6,8) A3 pregnene- 11p,17a,2l-triol-20-one were treated by the same pros,oso,ssa

7 cedure, giving respectively l'scarboxycyclopropano-(213'; ;3,6;3)-A -pregnene-17a,2l-diol-11,20-dione, 1-carboxycyclopropano (2',3;3a,4a) A pregnene 11,17,2ltriol-ZO-one and l-carboxycyclopropano-(2',3';5p,6fl)-A pregnene-l 1,3, 170:,21-iti01-ZO-0I16.

Example X The final products of Example IX were treated in ac cordance with Example VII, thus yielding the correspond? ing 2'1-acetates.

I claim:

1; A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and .a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; X is a member of the group consisting of hydrogen, fluorine and chlorine; and Y is selected from the group consisting of fi-hydroxyl and keto.

2. 1',l' dichlorocyclopropanm(2,3;3(1,410) A pregnene-17a,21'-diol-'1 1,20-dione.

5. Cyclopropano- (l,'2';3a,4a) A pregnene-11;3,l7p:, 2l-triol-20-one.

6. A compound of the following formula:

v Q W2 x-n X wherein R is selected from the group consisting of hydrogen anda hydrocarbon carboxylic acyl group of less than 12 carbon atoms; 'X is a member of the group consisting of hydrogen, fiuorine and chlorine; and Y is selected from the group consisting of fi-hydroxyl and keto.

7. 1,1'-dichlorocyclopropano-(2,3;5B,6fl) A pregnene- 17 a,21-diol-1 1,20-dione.

u '8. 1,l'-difluorocyclopropano-(2',3355,65) A '3 pregnene-'17a,2l-dio1-1 1,20dione.

9. 1',-l'adifluorocyclopropano-(2',3155,65) A preg nene-l lfi,17a,21-tri01-20-one.

l0. Cyclopropano-(1',2';5[3,6;3) A :,2141'101-20-0118.

11. A compound of the following formula:

pregnene-l lfi,

CHzOB CHzOR i= Y f-QH CHI-C 0 OR wherein R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R is a member of the group consisting of hydrogen and a lower alkyl group; and Y is selected from the group consisting of B-hydroxyl and keto.

17. l-carbethoxycyclopropano (2,3;5;8,6/8)-A -pregnene-l7a,2 1- diol-|l1,20-dione.

18. '1'scarbethoxycyclopropano (2',3';5;8,6p)-A -pregnene-llB,17a,21-triol-20-one.

20. l'-carboxycyclopropano (2,3;5,B,6;8) A preg- I16l1-l7 x,21-diOl-1 1,20-clione.

No references cited. 

1. A COMPOUND OF THE FOLLOWING FORMULA: 